The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity.
Since most D2.50N mutations show lower agonist affinity and become less active in response to agonist (Wilson et al., 2001), a protonated D2.50 appears to be incompatible with agonist binding, thus deprotonation is favored.
Similarly, a correlation between agonist affinity and agonist length has been previously shown in GABAA receptors (39).
Decreases in agonist affinity and in the maximal number of binding sites were recorded for all three receptor subtypes, although a slightly larger decrease in affinity was measured for κ-OR than for μ-OR and δ-OR.
To gain a deeper understanding of the properties that govern agonist affinity and efficacy, we investigated in detail how the different ligands that fit the new pharmacophore model interact with the receptor binding site.
We sought a mechanistic explanation for the decrease in agonist affinity and the maximal number of binding sites by adding to the analysis of the ligand-free simulations that of additional biased or unbiased MD simulations of antagonist-bound and agonist-bound, activated receptors conducted using the δ-OR ultra-high-resolution crystal structure as a model system.
The TCR activation threshold, agonist affinity discrimination and signal termination must therefore be tightly regulated.
28 The similarities and differences between the models were analyzed in detail with regards to experimental data on agonist affinity, efficacy, and effects of binding site mutations.
Concerning the molecular parameters for agonist affinity, receptor kinetics and rundown, our data rather favour the hypothesis of an involvement of the tertiary and quaternary structure of the whole receptor molecule than a restricted structural domain [32].
The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists.
